tbuckley/cabot-search huggingface dataset:
TIPS combined with lenvatinib and PD-1 inhibitor in patients with advanced HCC with symptomatic portal hypertension: A retrospective study.
Authors: Maoyuan Mu, Xiaobo Fu, Han Qi, Weiwei Jiang, Zixiong Chen, Fei Gao
Journal: Journal of Clinical Oncology (2023)

e14628 Background: Symptomatic portal hypertension (SPH) leads to a poor prognosis as a common complication in advanced hepatocellular carcinoma (HCC) patients due to cirrhosis or portal vein tumor thrombus. Although combined therapy including Lenvatinib and PD-1 inhibitors has shown valuable advantages in advanced HCC, the above strategy is limited by liver function impairment due to SPH complications such as variceal bleeding and refractory ascites. Transjugular intrahepatic portosystemic shunt (TIPS) directly relieves portal hypertension which may create a chance for advanced HCC patients with SPH to receive systemic therapy. Thus, TIPS plus following Lenvatinib and PD-1 inhibitor may serve as an effective anticancer modality. This study aimed to evaluate the efficacy and safety of TIPS combined with Lenvatinib and PD-1 inhibitor for advanced HCC patients with SPH. Methods: This retrospective study included thirteen advanced HCC with SPH patients who received TIPS combined with Lenvatinib and PD-1 inhibitor (Tislelizumab/Sintilimab) between January 2020 and January 2023. Main inclusion criteria: a confirmed HCC (BCLC stage C) based on the AASLD with either pathological or imaging findings; no previous systemic anticancer treatment; Child-Pugh score ≤10; ECOG status: 0-1. Portal hypertension with complications (variceal bleeding, refractory ascites). The outcome measures included objective response rate (ORR) (assessed with mRECIST v1.1), disease control rates (DCR), progression-free survival (PFS), overall survival (OS), SPH recurrence rate, and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: With a median follow-up of 6.5 months (range 2.3-19.0), 13 patients with a median age of 57 years (range: 33-70) were evaluable for response and toxicity. 3 (23.1%) patients with Tislelizumab and 10 (76.9%) with Sintilimab. 7 (53.8%) patients were classified as Child-Pugh A class. According to mRECIST v1.1, ORR was 38.5% (95%CI, 11.8%-61.6%) with 1CR and 4 PR, and the DCR was 53.8% (95%CI, 21.3%-73.4%). The median overall survival (OS) was 16.5 months (95%CI,16.1-17.0). The prevalence of rebleeding, ascites and hepatic encephalopathy, was 7.7 %, 15.4%, and 7.7%, respectively. Treatment-related adverse events were confined to grades 1-2 occurring in 3/13 (23.1%) patients as rash (2, 15.4%) and fatigue (1, 7.7%). There were no treatment-related serious adverse events. Conclusions: TIPS combined with Lenvatinib and PD-1 inhibitor demonstrated a valuable anti-cancer strategy for advanced HCC patients with SPH based on the low recurrence rate of SPH and acceptable side effects.
Phase 1 results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) or gemcitabine (gem) in advanced solid tumors.
Authors: Ryan C. Lynch, Pamela N. Munster, Gerald Steven Falchook, Monika Leigh Burness, Timothy A. Yap, Geoffrey Shapiro, David R. Spigel, Manish R. Patel, Kathleen N. Moore, Dejan Juric, Susan Doleman, William D. Bradley, Thomas J. O'Shea, Judson M. Englert, Markus F. Renschler, Nina Beri
Journal: Journal of Clinical Oncology (2023)

3099 Background: The MCT inhibitor CYT-0851 blocks lactate transport resulting in glycolytic cancer cell death. Monotherapy clinical activity has been previously reported in lymphoma and solid tumors. Preclinical studies assessing CYT-0851 with chemotherapy identified enhanced growth inhibition when combined with 5-FU or gem supporting clinical evaluation. Methods: Patients (pts) with solid tumors were treated with CYT-0851 + standard dosing of cape or gem in 21- and 28-day cycles, respectively, following a 3+3 design. The primary objective was to determine the MTD. Secondary objectives included: safety, PK, and anti-tumor activity by RECIST. Results: As of Feb 1, 2023, 14 pts (pancreatic n=9; ovarian n=5) were treated in 4 cohorts (100 - 400 mg QD) with cape. No DLTs occurred, and 400 mg QD was selected as the RP2D. 8 pts (57%) experienced a treatment-related adverse event (TRAE), including 2 (14%) with a G3/4 AE. The most common related AEs were primarily G1/2 and included fatigue (21%), nausea, decreased appetite, dry skin, mucosal inflammation and maculopapular rash (all 14%). 10 pts (sarcoma n=6; HNSCC n=1; ovarian n=1; pancreatic n=2) were treated in 2 cohorts (100, 200 mg QD) with gem. No DLTs occurred. Escalation is ongoing with up to 2 further cohorts. 9 pts (90%) experienced a TRAE, including 5 (50%) with a G3/4 AE which were primarily cytopenias. The most common TRAEs were fatigue (50%), anemia (50%), neutropenia (40%), thrombocytopenia (30%), nausea, pruritus, ALT/AST increased, neutrophil decreased and WBC decreased (all 20%). CYT-0851 exposure was similar between combination therapy and monotherapy. 8 pts in the cape cohorts were response-evaluable, including 3 with ovarian cancer. 1 pt with platinum-resistant ovarian cancer had a confirmed PR with treatment ongoing at 174 days. 7 pts had SD. 6 pts in the gem cohorts were response-evaluable. 1 pt with sarcoma had a confirmed PR, 4 pts had SD and 1 had PD. Conclusions: 400 mg QD was selected as the RP2D in combination with cape as no MTD was identified. Escalation of gem + CYT-0851 is ongoing to identify the MTD. Both combinations have demonstrated an acceptable safety and tolerability profile with no unanticipated toxicities at clinically active doses. Encouraging antitumor activity has been observed in heavily pre-treated pts with both regimens including pts with ovarian cancer in the cape combo. The cape cohort is being expanded with additional pts with ovarian cancer and will be presented. Clinical trial information: NCT03997968 .
A prospective non-randomized phase I trial of dendritic cell–based cryoimmunotherapy combined with checkpoint inhibitors in mCRPC.
Authors: Liv Cecilie Vestrheim Thomsen, Alfred Honoré, Bjorn T. Gjertsen, Astrid Børretzen, Lars Anders Reisæter, Bjarte Almås, Svein Inge Helle, Kristina Førde, Martin Biermann, Waqas Azeem, Benjamin Gabriel, Stian Knappskog, Ole Johan Halvorsen, Lars Akslen, Klaus Pantel, Sabine Riethdorf, Anne Margrete Øyan, Karl-Henning Kalland, Christian Beisland
Journal: Journal of Clinical Oncology (2023)

e14708 Background: Despite improvements, metastatic castration-resistant prostate cancer (mCRPC) still has dismal overall survival (OS). We treated 18 mCRPC patients with dendritic cell (DC)-based cryoimmunotherapy (CryoIT) as monotherapy or combined with checkpoint inhibitors to determine safety and immune response. Methods: mCRPC patients were biopsied before cryoablation, and subsequently injected intratumorally with autologous immature DCs. DC doses were escalated in a 3+3 design (n=9) followed by dose expansion combined with either ipilimumab (n=6) or pembrolizumab (n=3). The disease burden was assessed by PSA values, iRECISTv1.1 (PET/CT, MRI and bone scintigraphy at baseline, 14, 22 and 46 weeks) and circulating tumor cells (CTC; CellSearch). Immune response was monitored by ultradeep T-cell receptor sequencing. Results: The patients had aggressive cancer, with ISUP grade group 4 and 5 in 72% (13/18) at diagnosis and in 100% at inclusion. At baseline, higher ALP correlated with higher regulatory T cells (p=0.047), FoxP3+/CD3+ratios (p=0.014) and FoxP3+/CD8+ratios (p=0.004) in tissues. Median OS and progression-free survival (PFS) were 40.7 and 10.5 months, respectively. Of the 8 patients alive 43 to 85 months post-CryoIT, 7 had progressed and received other treatment. Early decreases in PSA (p=0.002) and LDH (p=0.01) levels 6 weeks after CryoIT indicated better outcomes at 22 weeks. Longer OS correlated with lower tissue ratios of CD4+/CD3+cells (p=0.002) and CD4+/CD8+cells (p=0.007). All patients with increased numbers of new T-cell clonotypes after CryoIT and CTC at the pretreatment level of 1-4 cells/ 7.5 mL blood changed to negative during follow-up up to 72 weeks. Conclusions: CryoIT demonstrates non-inferior OS and PFS compared to other mCRPC trials, and therapy response was suggested by decreased CTCs and induction of new T-cell clonotypes post-CryoIT. Lower CD4 + cell fractions of lymphocytes in the TME indicate better OS after CryoIT. CryoIT appears not to decrease effects of post-treatment recurrence therapies. Clinical trial information: NCT02423928 . [Table: see text]
Safety and efficacy of immune checkpoint inhibitors (ICIs) in patients (pts) with cardiac metastases (mets) from solid tumors.
Authors: Amin Nassar, Sarah Abou Alaiwi, Talal El Zarif, Ryan Austin Denu, Salim S. Hayek, Rachel S Goodman, Rachel Woodford, Tomas G. Neilan, Tarek Haykal, Yuji Kojima, Alexandra Trevino, Gavin Hui, Ankita Tandon, Edward El-Am, Arjun Mittra, Javier Baena, Arrush Choudhary, Shirly Grynberg, Toni K. Choueiri, Abdul Rafeh Naqash
Journal: Journal of Clinical Oncology (2023)

2653 Background: Given underlying differences in the tumor microenvironment across metastatic sites, ICIs demonstrate variable efficacy depending on sites of met involvement. Data on the safety and outcomes of pts on ICIs with cardiac mets are limited. Methods: In an international multi-center retrospective study, pts with solid tumors and baseline mets to the heart who had received ≥1 cycle of ICIs were included. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Objective response rates (ORR) were evaluated by RECIST1.1 when available. Median overall survival (mOS) and median progression-free survival (mPFS) were calculated from time of ICI initiation using the Kaplan-Meier method. Results: 110 pts across 20 institutions were identified with a median follow-up of 36 (95% CI 26-51) months. Melanoma (38%, n=42) and non-small cell lung cancer (NSCLC, 24%, n=26) were the most common cancers. Median age at ICI initiation was 65 (IQR: 59-75) years and 29% (n=26) received combination ICI therapy with anti-PD1 and anti-CTLA4. Overall, 62% (n=68) received ICIs as 1 st line. The mets were mostly located in the atria (37%, n=41) and ventricles (35%, n=39). At ICI initiation, 21% (n=23) had a cardiac thrombus. Of 78 pts with available echocardiographic data at time of ICI initiation, the mean ejection fraction was 61+/- 7.1%. Cardiology referrals and cardiac MRIs since time of cancer diagnosis were completed on 53% (n=58) and 47% (n=52) of pts, respectively. Overall, 36.4% (n=40) of pts had cardiac complications from the mets, including arrhythmias (13%, n=14), arterial/venous emboli (3.6%, n=4), and cardiac tamponade (2.7%, n=3). For NSCLC, ORR, mPFS (95% CI), and mOS (95% CI) were 23%, 4.4 months (3.0-7.5), and 9.9 months (5.9-14.7), respectively. For melanoma, ORR, mPFS, and mOS were 35.7%, 9.1 months (5.2-20), and 29 months (14-58), respectively. Cardiac met ORRs for NSCLC and melanoma were 27% and 43%, respectively. 74% (N=71/96) of pts with evaluable response data had concordant response in the burden of overall disease and cardiac disease. IrAEs are shown. Conclusions: Although cardiac mets are frequently associated with cardiac complications, ICIs demonstrate meaningful efficacy with no overtly concerning safety signals. Close to three-quarter of pts have concordant response in the overall disease and cardiac disease burden. Multi-disciplinary approach involving cardiologists and oncologists need to be implemented to appropriately manage pts with cardiac mets. [Table: see text]
Precision immuno-oncology (IO) ISH/IF multiplex panel: Spatial detection of cytokines and IO biomarkers.
Authors: Bhavika Patel, Brenna Dennison, Stephanie Allen, Jacob Stapleton, Roni Archuleta, Mary Lou Rath, Navi Mehra, Sameer S. Talwalkar
Journal: Journal of Clinical Oncology (2023)

e14654 Background: Cytokines have a large impact on the tumor microenvironment by affecting cell growth, survival, inflammation, and differentiation. Understanding the spatial biology within the tumor microenvironment, including the cytokine organization within specific cell types, can lead to better treatment plans for patients. Methods: We developed a hybrid multiplex panel, using RNA in-situ hybridization (ISH) and immunofluorescence (IF) to investigate the spatial biology of the tumor microenvironment. This panel also enabled us to simultaneously detect the RNA of cytokines and protein of specific immuno-oncology (IO) biomarkers. This allows us to visualize spatially, not only the organization of cell types but also to identify the cellular sources of specific cytokines. In this study, we analyzed the tumor microenvironment of samples from non-small cell lung cancer (NSCLC) and breast cancer in two panels for cytokine RNAs and IO protein biomarkers. Panel 1 included TNFa and IL-2 cytokines combined with CD68 and CD163 IO protein biomarkers. Panel 2 consisted of IL-6 and IL-2 cytokines with PAX5 and CD3 IO protein biomarkers. Staining was completed on the Leica Bond RX autostainer, and slides were scanned using the PhenoImager Fusion. Visiopharm software wasused to analyze the tumor microenvironment of tissue samples and localize cytokines in specific cell types. Results: CD163 positive macrophages (M2 phenotype) were seen predominantly within the tumors (NSCLC and breast cancer) whereas CD68 positive macrophages were identified towards the periphery in the non-tumor microenvironment. NSCLC tumor cells showed higher expression levels of IL-2, IL-6 and TNFa compared to breast cancer tumor cells. Predominance of CD3 positive T cells was noted with relative lack of PAX5 positive B cells within both NSCLC and breast cancer tumors. Multiplexing enabled assessment of relative expression levels of IL-2, IL-6 and TNFa in T lymphocytes and macrophages and TNFa in dendritic cells. Conclusions: Our hybrid multiplex panel can provide insights into the visualization of spatial organization of tumor microenvironment. It also enables semi-quantitative assessments for the expression levels of cytokines and their relative expression within tumor and immune cells, thereby helping to correlate response to treatment, especially with checkpoint inhibitors.
PD-1 inhibitors combined with radiotherapy and GM-CSF, sequentially followed by IL-2 (PRaG 2.0) regimen in advanced refractory solid tumors: A prospective, multicenter, single-arm clinical trial.
Authors: Pengfei Xing, Jiabao Yang, Meiling Xu, Jian Wang, Dali Han, Yuehong Kong, Junjun Zhang, Liyuan Zhang
Journal: Journal of Clinical Oncology (2023)

2603 Background: Low frequency of durable responses in patients treated with immune checkpoint inhibitors demands taking complementary strategies in order to boost immune responses against cancer. Our previous PRaG trial also demonstrated that PD-1 inhibitors in combination with radiotherapy and granulocyte macrophage-colony stimulating factor (GM-CSF) could improve clinical response in patients with advanced refractory solid tumors (ChiCTR1900026175). In an effort to further enhance efficacy, we conducted the PRaG 2.0 trial (ClinicalTrials.gov: NCT04892498) and optimized the PRaG regimen by incorporating interleukin-2 (IL-2). Methods: The PRaG 2.0 regimen was administered to patients with advanced refractory solid tumors who lacked or were unable to tolerate standard-of-care treatments. A treatment cycle consisted of radiotherapy (5 or 8Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 7 days, and then sequentially followed by IL-2 2million IU SC once daily for 7 days. PRaG 2.0 regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose of normal tissues. Patients who could not continue radiotherapy and had not yet developed progression disease (PD) allowed PD-1 inhibitors to be continued as maintenance therapy until PD or unacceptable toxicity but no more than one year. The primary endpoint was Progression-Free Survival (PFS). Results: As of 31st October 2022, 51 patients were enrolled in the study, and 42 completed at least one tumor assessment. The median Progression-Free Survival (PFS) was 5.8 months, and the median overall survival (OS) was 13.5 months. The objective response rate (ORR) was 21.4%, and the disease control rate (DCR) was 61.9% according to RECIST version 1.1. Lower plasma levels of Interleukin (IL)-6 and IL-17 at baseline were found to be associated with improved PFS. Treatment-related adverse events (TRAE) experienced in 34 of 42 (78.6%) patients, with 4 patients (9.5%) experiencing Grade ≥ 3 TRAEs. TRAEs leading to discontinuation of all study treatments occurred in three patients (7.1%). Conclusions: The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with radiotherapy, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors, with an acceptable benefit/risk profile. Clinical trial information: NCT04892498 .
Molecular and immune profiling of <i>TP53</i>-mutated ovarian cancers with non-<i>BRCA1/</i>2 homologous recombination gene alterations.
Authors: Kyle C. Strickland, Rebecca A. Previs, Zachary D Wallen, Mary K Nesline, Heidi Chwan Ko, Sarabjot Pabla, Stephanie Hastings, Taylor J. Jensen, Prasanth Reddy, Eric A Severson, Shakti Ramkissoon
Journal: Journal of Clinical Oncology (2023)

5579 Background: Molecular alterations in homologous recombination (HR) pathway genes lead to HR deficiency (HRD) in ~50% of high grade serous ovarian carcinomas (HGSOC). The immune microenvironment of BRCA1/2-mutated HGSOC has been extensively characterized, in contrast to tumors with mutations in other HR genes. We evaluated a cohort of epithelial ovarian cancers (EOC) enriched for HGSOC and compared molecular and immune signatures of tumors with BRCA1/2 mutations ( BRCAm) to those with non-BRCA1/2 HR gene mutations (NBHRD). Methods: We characterized 173 EOC by comprehensive genomic and immune profiling (CGIP) using panel-based next-generation DNA (523 genes) and RNA sequencing (384 genes), respectively. We enriched for HGSOC by selecting for TP53 mutations and excluding tumors with non-serous histology or any mutation in POLE, MLH1, PMS2, MSH2, MSH6, or nucleotide excision repair genes. Tumors lacking BRCA1/2-mutations were classified as NBHRD if a reportable mutation was present in canonical HR genes. Mutational burden (TMB, mut/Mb) was estimated from detected SNV/indels. We calculated immune-related expression signatures, including tumor immunogenicity score (TIGS), cellular proliferation (CP), and cancer testis antigen burden (CTAB). PD-L1 expression was assessed by tumor proportion score (TPS) following 22C3 immunohistochemistry. Differences in TMB, TIGS, CP, CTAB, PD-L1 and gene expression rank were tested for using Wilcoxon rank-sum test. Results: Of 173 EOC, 84 cases had complete CGIP, including 11 (13%) BRCAm, 7 (8%) NBHRD (Table), and 66 (79%) lacking HR gene alterations. On average, NBHRD tumors harbored lower TMB (4.1±2.3 vs. 6.6±2.3 vs. p=0.03) and elevated TIGS (59.1±16.2 vs. 41.7±16.2 p=0.044) compared to BRCAm tumors. We found no difference in PD-L1 (p=0.21), CP (p=0.26), or CTAB (p=0.48). Expression changes were identified in 32 immune genes, of which 31 (97%) were substantially up-regulated (1.3-3.3 fold) in NBHRD compared to BRCAm tumors. Conclusions: Our findings showed our cohort of NBHRD tumors were more immunogenic but less mutagenic than BRCAm tumors, implying enhanced immunogenicity unrelated to neoantigen load. Given that immune checkpoint inhibitors have shown limited efficacy in ovarian cancer, our data suggest NBHRD tumors may have stronger and possibly distinct immune escape mechanisms compared to BRCAm tumors. [Table: see text]
Pathway enrichment analysis in tumors with high mutation burdens and interferon-γ signature expression: A pancancer analysis.
Authors: Xuanyi Li, Ben Ho Park, Justin M. Balko, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2023)

3138 Background: Tumor mutation burden (TMB) correlates with immunotherapy response, but outcomes still vary in high TMB cancers, and many high TMB tumors lack T cell infiltration. Here, we assessed gene expression signatures of high TMB, including both inflamed and non-inflamed tumors (defined by interferon-γ [IFN-γ] gene signatures). Methods: Gene set enrichment analysis (GSEA) was assessed from RNA-sequencing data in tumors in TCGA. TMB and IFN-γ signature score were assessed by previously published methods. We performed GSEA on high vs low TMB tumors, and further stratified by high vs low IFN-γ signature expression within high TMB tumors. We validated results in Tempus RNA-sequencing data from 264 patients at Vanderbilt. Results: 4020 TCGA cases in non-small cell lung, melanoma, bladder, head and neck, kidney, and colorectal cancer were included. Major signatures upregulated in the high TMB group included cell cycle signaling, nuclear protein/mRNA export, cholesterol biosynthetics, and ubiquitin signaling. High TMB/high IFN-γ signature tumors were enriched in immune-related pathways (neutrophil and monocyte chemotaxis, T cell activation and proliferation, and interleukin-1 secretion), and non-immune pathways including cAMP metabolic process and phosphatidylinositol signaling. High TMB/low IFN-γ signature tumors had enriched pathways in nonsense mediated decay, electron transport chain/oxidative phosphorylation, and mitochondrial translational disassembly. 264 tumors from Vanderbilt were used for validation; pathways including cholesterol biosynthetics also correlated with immunotherapy response. Conclusions: High TMB tumors were enriched in pathways such as ubiquitin signaling, which could regulate immune cell function in antitumor immunity. Within high TMB cancers, tumors with higher IFN-γ signatures have enriched immune-related, and metabolic pathways, which could suggest novel therapeutic targets to make high TMB/ low IFN-γ tumors more immunogenic.